Inguinal lymph node metastases from rectal adenocarcinoma: a systematic review

Study selection

The PRISMA diagram (Fig. 1) summarises the study selection process. The initial search yielded 620 references, from which 157 duplicates were removed. The remaining 463 records were screened down to 43 studies which underwent full-text review. Eleven studies reported in languages other than English [18,19,20,21,22,23,24,25,26,27,28], five case reports [29,30,31,32,33], seven irrelevant studies [4, 34,35,36,37,38,39] and three reports which were abstracts only [40,41,42] were excluded. Two further studies for inclusion were identified through forward chaining of citations. In total, 19 studies met the eligibility criteria and were included in the review [2, 8, 9, 11, 43,44,45,46,47,48,49,50,51,52,53,54,55,56,57].

Fig. 1figure 1Study characteristics

The included studies comprise 18 case series: two are multicentre, and the remaining 16 are single-centre. One study is population-based and uses national registry data. In total, 487 patients with inguinal lymph node metastases from rectal adenocarcinoma are included. Time periods of patient recruitment in the included studies range widely, the earliest starting in 1949 and the latest included patients treated up to 2020. Table 1 summarises the study characteristics.

Table 1 Study characteristicsBias and quality analysis

Results of the bias and quality analysis are displayed in Table 2. Several studies demonstrated similar drawbacks, such as incomplete reporting of long-term outcomes and patient demographics. However, most studies scored highly for quality and presented sufficient data to limit bias.

Table 2 Risk of bias analysisPatient and primary tumour characteristics

Table 3 summarises the characteristics of the included patients and primary rectal tumours. Rectal tumours tended to be very low, with a pooled mean distance from the anal verge of 1.1 cm, despite 20.8% of tumours being located more than 5 cm from the anal verge. Malignant invasion of the dentate line was common (76%), and tumours were more likely to be locally advanced (81.6% T3–T4 disease). However, involved mesorectal lymph nodes were not universal; 32% of patients had no mesorectal nodal involvement. Within the included patients, unilateral ILNM were more prevalent than bilateral ILNM (72.1% vs 27.9%).

Table 3 Characteristics of patients and primary rectal tumoursPresentation

Just two studies report on the incidence of ILNM in rectal adenocarcinoma [8, 46]. When pooled, 80 patients from 22,130 cases of rectal cancer demonstrated ILNM, giving a pooled incidence of 0.36%. Within the included single-centre case series, a pooled mean of 17.8 cases was identified for every 10 years of the study periods. This figure can be extrapolated to suggest that large tertiary cancer centres see, on average, 1.8 cases of ILNM from rectal adenocarcinomas each year.

The most common definition of a metachronous presentation, as defined by primary studies, was the identification of ILNM within 1 year of the primary rectal tumour. Given this definition, synchronous ILNM had equal representation to metachronous presentations in the data set (51.2% vs 48.8%, respectively).

When reported, preoperative diagnosis of ILNM was with computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FDG-PET). The most common definition of a clinically positive ILN was FDG-PET positivity, abnormal morphology or a short-axis diameter of 10 mm or greater [49, 52, 55]. Within the included studies, there is variable use of lymph node biopsy to histologically confirm metastases prior to ILN dissection, and no clear consensus is demonstrated [40, 44, 48, 53].

Out of 399 patients for whom it was reported, 196 (49.1%) were diagnosed with isolated ILNM metastases only, whilst 203 (51.9%) had distant solid organ metastases in addition to ILNM. Regarding synchronous ILNM only, 63.6% of patients had disease isolated to just the inguinal lymph nodes (isolated synchronous inguinal lymph node metastases, SILNM), and 36.4% had ILNM in addition to distant organ metastases (synchronous inguinal lymph node metastases and distant organ metastases, SILNM&DOM). For metachronous presentations, 24.5% were isolated (isolated metachronous inguinal lymph node metastases, MILNM), and 80.3% had distant metastases (metachronous inguinal lymph node metastases and distant organ metastases, MILNM&DOM). Given the expected differences in the treatment and prognosis of these four presentations, all outcomes were analysed in these four distinct groups.

TreatmentChemoradiotherapy

When reported, 95.1% (174 of 183) of patients from all groups had a radical rectal resection with curative intent. Eight of the remaining nine patients belonged to the SILNM&DOM group and were treated palliatively because of the presence of distant metastatic disease on presentation. The final patient demonstrated a complete clinical response of both the primary tumour and the ILNM to chemoradiotherapy and was successfully managed with a watch-and-wait approach.

The heterogeneity of the included studies limits meaningful analysis regarding the use of neoadjuvant chemoradiotherapy (NACR). The time period of patient recruitment and TNM staging vary widely. Accepting these limitations, pooled rates of NACR for isolated SILNM and SILNM&DOM are 65.2% and 92%, respectively. For isolated MILNM, 50% had NACR prior to rectal resection. For MILNM&DOM cases, reporting of NACR was insufficient to calculate summary rates.

External beam radiotherapy targeted at the inguinal nodes was sporadically reported upon. Therefore, mean rates for each group are not calculable. Abd El Aziz et al. report this in the greatest detail and use a similar dose (median 50.4 Gy, range 45–66) for both inguinal and rectum-targeted radiotherapy. The mean rate of use for all patients was 45.7%, but studies were polarised and reported high (79–100%) or low usage (0–3%), suggesting significant centre-specific variation in protocols.

Surgical treatment of ILNM

Ten studies reported on the surgical excision of ILNM, including 204 patients [9, 11, 40, 43, 45, 49, 50, 53, 55, 57]. Only two studies describe the surgical technique in detail [49, 53]. Both describe excisions which included both clinically positive and negative nodes. Abd El Aziz et al. [11] report the excision of clinically positive nodes only in some cases and the complete dissection of superficial inguinal lymph nodes in others. Furthermore, the depth of dissection was limited to the superficial inguinal nodes in two studies [40, 45], but Tanabe et al. and Hasegawa et al. describe additional dissection of the deep inguinal nodes [49, 53]. Abd El Aziz et al. also describe the use of minimally invasive lymph node dissection, an approach utilising laparoscopic ports within the femoral triangle [58, 59]. The remaining studies do not detail the technique. Given the available data, comparative analysis of long-term outcomes by surgical technique is not possible.

Three studies reported on postoperative complications of groin dissection for ILNM [47, 49, 55]. Clavien–Dindo [60] (CD) grade II and III complications were developed by 20.5% (8/39) and 17.9% (7/39) of cases, respectively. No CD grade IV or higher complications were reported. Complications included lymphorrhoea, seroma, wound infection and lymphoedema.

Recurrence and survival

Heterogeneity and limited reporting in primary studies precluded comparative or proportional meta-analyses for recurrence or survival outcomes. Data synthesis is, therefore, descriptive.

Studies published before 2010 either did not report or reported poor survival outcomes for patients with any form of ILNM [2, 46, 50, 51, 54]. The largest study from this period, Graham et al. [46], considered treatment “predominantly palliative” given coexistent advanced pelvic or distant disease. Luna-Perez et al. [50] also report 0% 5-year overall survival and conclude that “only palliative treatment should be indicated”.

However, more recent studies have demonstrated improved outcomes, particularly for isolated ILNM. For isolated SILNM and MILNM, 1-, 3- and 5-year overall survival reported in the largest and most recent series are 82–100%, 53–86% and 53–78%, respectively [9, 11, 47, 49, 53]. Survival is worse for patients with concurrent distant organ metastases, whether this is found synchronously or metachronously. Abd El Aziz et al. included eight patients with SILNM&DOM who underwent NACR, curative intent resection and surgical excision of affected inguinal lymph nodes and reported 47% and 21% 3-year and 5-year overall survival, respectively. Yeo et al. report on seven patients with MILNM&DOM and demonstrate 0% 3- and 5-year survival with a mean overall survival of 14 ± 6.9 months from the time of recurrence.

When focusing on isolated SILNM, Hasegawa et al. and Abd El Aziz et al. report the highest 5-year overall survival for this cohort at 77.5% and 53%, respectively. All but one patient from both groups underwent neoadjuvant chemotherapy, and 25/29 (86.2%) underwent radiotherapy. Abd El Aziz et al. report radiotherapy was targeted rectally and at the inguinal region. Hasegawa et al. do not report on the targeted site of radiotherapy, but state all included patients underwent surgical excision of ILNM in addition to curative-intent radical rectal resection. Eight of 14 (57.1%) patients in the study by Abd El Aziz et al. had limited excision of clinically positive nodes, and the remainder from both studies had more extensive ILN dissection. Nine patients in each group had adjuvant chemotherapy. Within the patients reported on by Abd El Aziz et al., six patients developed distant recurrence, and two developed inguinal region recurrence. Both inguinal recurrences were contralateral to the operated side. For Hasegawa et al., six patients developed recurrence, four within the pelvis and two at distant sites. No inguinal recurrences were reported.

For isolated MILNM, no modern studies report survival and recurrence figures specific to this cohort. Three studies [11, 40, 53] report treating such patients with chemotherapy and ILN surgical dissection. One of these studies pooled survival rates with isolated SILNM and reported a 5-year overall survival of 55.3% for 31 patients [53]. More specific oncological outcome data for this cohort is not available in the current literature.

ILNM response to chemoradiotherapy

Hasegawa et al. [49] performed PET-CT in all 15 patients in their series after NACR. All five patients without FDG uptake in ILN after NACR had no histopathological evidence of disease in the inguinal nodes retrieved during dissection. In the case of persistently FDG-avid PET-CT, just 4/9 (44.4%) were histologically positive for metastases. Within the isolated SILNM cohort, Abd El Aziz et al. reported 9/13 (69.2%) patients had histologically positive nodes after NACR.

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